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									   HIV Pathogenesis and
Natural Course of the Disease
                    Unit 4
   HIV Care and ART: A Course for Physicians
Learning Objectives
■ Discuss HIV molecular biology and virology
■ Describe immunological response against
  infections
■ Explain the effect of HIV on the immune system
  and how HIV establishes a chronic infection
■ Identify characteristics that make HIV disease
  chronic and incurable
■ Understand the natural course of the disease

 Pathogenesis and Natural Course of the Disease    2
                             Virology of HIV




Pathogenesis and Natural Course of the Disease   3
Characteristics of HIV
■ Classification
     ■ Family of retroviruses (RNA -> DNA -> RNA)
     ■ Subfamily of lente (slow) viruses

■ Cytopathic to cells that replicate it
■ Infects many cells types and is latent in some cells
■ Infects and depletes CD4 lymphocytes
■ Causes cell-mediated immunosuppression

 Pathogenesis and Natural Course of the Disease     4
HIV Strains
■ HIV-1 Group M (main), the cause of the AIDS
  epidemic
■ HIV-2, a less virulent retrovirus causing an
  epidemic in West Africa




 Pathogenesis and Natural Course of the Disease   5
HIV-1 and HIV-2 Differ in Multiple
Ways
■ Accessory genes
     ■ HIV-1 vpu
     ■ HIV-2 vpx

■ Distribution
     ■ HIV-1 – global pandemic
     ■ HIV-2 – West Africa

■ Rate of progression of severe immunosuppression
     ■ HIV-1 – median time to AIDS = 10 years
     ■ HIV-2 – median time to AIDS = longer, but ?


 Pathogenesis and Natural Course of the Disease      6
Classification of HIV-1
■ Groups
     ■ M (major) with 9 subtypes (clades)
     ■ O (outlier)
     ■ N (reported only in Cameroon)

■ Group M’s clades (related viruses)
     ■ Named with letters A to K, with many recombinants between parts of
       HIV from two clades
     ■ Differ in geographic distribution
     ■ Differ from each other by about 30% in the env coding sequences
       and 14% of the gag code sequences


 Pathogenesis and Natural Course of the Disease                          7
HIV Clades
■ HIV rapidly evolves by two mechanisms:
    ■ Mutation - changes in single nucleosides of the RNA
    ■ Recombination – combinations of long RNA sequences from two
      distinct HIV strains

■ Distinct genetic subgroups, or clades, of the M group of HIV
  have evolved and become dominate in specific geographic
  regions
    ■ A in Central Africa
    ■ B in North American and Europe
    ■ C in Southern and Eastern Africa

■ Several clades (e.g., A/G ad A/E) are recombinants

Pathogenesis and Natural Course of the Disease                      8
Geographic Distribution




 Pathogenesis and Natural Course of the Disease   9
Structure of HIV




 Pathogenesis and Natural Course of the Disease   10
Characteristics of HIV
■ HIV infect cells that express CD4 receptor
  molecules
■ CD-4 receptor molecules are expressed by T-
  helper cells and monocyte-macrophage cell lines
■ Successful entry of the virus to a target cell also
  requires cellular co-receptors




 Pathogenesis and Natural Course of the Disease         11
Characteristics of HIV (2)
■ A fusion co-receptor is designated CXCR5 for T-
  cell tropic stain and CCR4 for monocyte-
  macrophage tropic strains
■ The receptor and co-receptors of CD4 cells interact
  with HIV’s gp-120 and gp-41 proteins during entry
  into a cell




 Pathogenesis and Natural Course of the Disease     12
          HIV Receptors
            HIV Receptors
HIV and Cellular Receptors




     Levy JA, NEJM, 335(20); 1528-1530


 Pathogenesis and Natural Course of the Disease   13
Role of Chemokine Receptors in HIV Entry
Host Cell Membrane Fusion Via CXCR4
Pathogenesis and Natural Course of the Disease   15
Pathogenesis and Natural Course of the Disease   16
Pathogenesis and Natural Course of the Disease   17
                                                 Cell cytoplasm




             Cell nucleus




Pathogenesis and Natural Course of the Disease            19
Pathogenesis and Natural Course of the Disease   20
Life Cycle of HIV: Replication
■ Reverse transcription converse HIV RNA into proviral DNA
■ Importation to cell nucleus
■ Integration of proviral to host-cell DNA
■ Cellular activation causes transcription (copying) of HIV
  DNA back to RNA
■ Some RNA translated to HIV proteins
■ Other RNA moved to cell membrane
■ HIV assembled under cell membrane and budded from cell
■ Proteases convert immature to infectious HIV

 Pathogenesis and Natural Course of the Disease               21
             HIV life of HIV
Summary of Life Cycle cycle and Sites of
Drug Action




Fusion-Inhibitors




   Pathogenesis and Natural Course of the Disease   22
Characteristics of HIV
Once infection is established, the virus homes itself
mainly in the lymphoid and, to a lesser extent, in the
circulation.




 Pathogenesis and Natural Course of the Disease     23
Early Phases of HIV Entry and Replication
at Mucosal Surfaces


Cell free
  HIV                                                       CD40—CD40


                                                                           T-cell
                  Immature Dendritic
                  cell                                                      PEP

             Skin or                 Via lymphatics or                   Burst of HIV
             mucosa                  circulation                          replication
                        24 hours                         48 hours
     1.     HIV co receptors,       2.   Selective of      3.   Mature Dendritic
            CD4 + chemokine              macrophage-            cell in regional LN
            receptor CC5                 tropic HIV             undergoes a single
                                                                replication, which
                                                                transfers HIV to T-
                                                                cell
 Pathogenesis and Natural Course of the Disease                                       24
Spread of HIV in Host Tissues
Enhanced: Dendritic Cell’s HIV Infectivity
to CD4 T-cell




                                          CD4


 Pathogenesis and Natural Course of the Disease   26
                    Immunology and HIV
                         Infection




Pathogenesis and Natural Course of the Disease   27
Types of Normal Immune Responses
■ Innate – non-specific, “natural,” no prior contact
  required
    ■ Mediated through neutrophils, macrophages, circulating
      binding proteins, and natural killer lymphocytes

■ Acquired – specific, learned from contact with
  pathogens
    ■ Mediated through T (cellular signalizing) and B (antibody
      producing) lymphocytes and macrophages



Pathogenesis and Natural Course of the Disease              28
The Normal Immune Response
■ Normal host defense in response to a foreign
  antigen culminates in a rapid and efficient
  elimination of a non-self substance
■ The process of elimination of a foreign antigen
  involves effector-cell activity and their interaction
  through soluble cellular secretions (cytokines)




Pathogenesis and Natural Course of the Disease            29
Specific Normal Immune Response




Pathogenesis and Natural Course of the Disease   30
Normal Immune-Cell Interaction

                                                  plasma
CD-4-4
                                                     CTL

                                                      CTL




 Pathogenesis and Natural Course of the Disease            31
Specific Immune Response




Pathogenesis and Natural Course of the Disease   32
Peculiar Characteristics of HIV
HIV is a unique infection in that:
■ The virus is not cleared, except partially in the
  early period of infection
■ A chronic infection is established, and it persists
  with varying degrees of viral replication. The viral
  replication continues for about eight to ten years
  before bringing in significant immuno-suppresion
■ There is no virological latency


 Pathogenesis and Natural Course of the Disease       33
Infected CD4 T-lymphocyte

                                           HIV




Modified; South Carolina Medical Library
Viral Dynamics of HIV Infection
■ Viral replication is continuous in all stages (early,
  during clinical latency and in advanced stages)
■ Half life of a virion is about 6 hours, while an
  infected cell has a life span of 1.6 days
■ Daily about 1010 virions are produced and cleared
  from the circulation
■ Average generation time of HIV is 2.6 days



 Pathogenesis and Natural Course of the Disease           35
Viral Set Point
■ The level of steady-state viremia (set-point) at six
  months to one year after infection has and
  important prognostic implication for progression of
  HIV disease
■ Those with a high viral set-point have faster
  progression to AIDS, if not treated




 Pathogenesis and Natural Course of the Disease     36
Reasons for Persistent Viremia

Despite robust immune reaction, HIV evades
elimination by the immune system due to:
     ■ High level of viral mutation
     ■ Large pool of latently infected cells that cannot be
       eliminated by viral-specific CTLs
     ■ Virus homes in lymphoid organs, while antibody is in the
       circulation
     ■ Exhaustion of CD8 T-lymphocytes by excessive antigen
       stimulation


 Pathogenesis and Natural Course of the Disease               37
Reasons for Persistent Viremia (2)

     ■ Down regulation of HLA-1 molecule in HIV infected cells
     ■ HIV attacks CD-4 T-cells, which are central to both
       humoral and-cell mediated immunity
     ■ HIV seeds itself in areas of the body where sufficient
       antibodies might not reach, e.g., the central nervous
       system




 Pathogenesis and Natural Course of the Disease                 38
Pathogenesis of HIV
■ HIV infection is a disease characterized by a
  profound immunodeficiency from progressive
  decline of T-helper cells
■ The pathogenetic mechanism of HIV disease is
  multifactorial and multiphasic and it differs in
  different stage of the disease




 Pathogenesis and Natural Course of the Disease      39
Effects of Cellular Activation
■ Quiescent but infected CD4 T-cells start to
  transcript, making viral spread more efficient
■ Cellular activation induces expression of receptors
  for HIV
■ Chronic stimulation favors programmed cell death
  (apoptosis) to CD4, CD8 and B-cells
■ Significant increase in the release of cytokines



 Pathogenesis and Natural Course of the Disease      40
Effects of Cellular Activation (2)
■ Brings about up-regulation of viral expression and
  cellular activation
■ Initiates auto-immune phenomena
■ Brings about compromised immune response to
  broad spectrum of antigens
■ Co-infection (TB, CMV, etc.) also induces viral
  replication



 Pathogenesis and Natural Course of the Disease     41
Cytokines in HIV
■ The immune system is regulated by a complex of
  immuno-regulatory cytokines
■ Cytokines are cellular products that induce or
  suppress cellular activity
■ Inducers of HIV expression include: IL-1, IL-2, IL-3,
  IL-6, IL-12, TNF-Alfa, TNL-beta, M-CSF and GM-
  CSF
■ The most potent inducers are pro-inflammatory
  cytokines, TNF-Alfa, IL-1and IL-6, which are
  products of macrophages

 Pathogenesis and Natural Course of the Disease     42
Cytokines in HIV (2)
■ T-helper cells are classified as TH-1 and TH-2
  based on the type cytokines they release
■ TH-1 type secrete IL-2 and INF-Alfa, which favor
  cell-mediated immune response
■ TH-2 type secrete IL-4, IL-5 and IL-10, which favor
  humoral immune response
■ HIV-infected individuals show decreased TH-1 type
  response in relation to TH-2


 Pathogenesis and Natural Course of the Disease      43
Effect of IL-2




 Pathogenesis and Natural Course of the Disease   44
T-cell Abnormalities
■ Late in the course of illness, there are qualitative
  and quantitative abnormalities
■ T-cell abnormalities detected in the course of the
  illness are manifested as CD4 and CD8
  abnormalities




 Pathogenesis and Natural Course of the Disease          45
CD4 Cell Abnormalities
■ Defective T-cell cloning and colony-forming
  efficiency
■ Impaired expression of IL-2
■ Defective IL-2 and INF-Alfa production
■ Decreased help to B-cells in production of
  immunogloblins
■ Marked reduction in their number


 Pathogenesis and Natural Course of the Disease   46
CD8 Cell Abnormalities
■ Remain high after primary infection and throughout
  the latent period
■ In advanced stage, there is marked reduction
■ HIV-specific clones of CD8 CTLs that are present
  in the early phase of illness disappear in advanced
  period
■ In the face of depleting CD4, the homeostatic
  mechanism responsible for maintaining total T-
  cells in a normal range replaces CD8, leading to
  CD8 lymphocytosis

 Pathogenesis and Natural Course of the Disease      47
Mechanism of CD4 Cell Depletion
■ HIV-mediated direct cytopathicity (singe cell killing)
■ HIV-mediated syncytia formation
■ Defect in CD4 T-cell regeneration in relation to the
  rate of destruction
■ Maintenance of homeostasis of total T-
  lymphocytes (decreased CD4, increased CD8)




 Pathogenesis and Natural Course of the Disease      48
Mechanism of CD4 Cell Depletion (2)
■ HIV-specific immune response (killing of virally
  infected and innocent cells)
■ Auto-immune mechanism
■ Programmed cell death (apoptosis)




 Pathogenesis and Natural Course of the Disease      49
Apoptosis (Programmed Cell Death)




Guisoppe et.al. NEJM 328,1993
B-cell Activity in HIV
■ There is no quantitative abnormality
■ Has abnormal activation with spontaneous
  proliferation and IG, IL-6 and TNF-Alfa secretion
■ B-cells are defective for antigen stimulation
■ HIV can directly stimulate B-cells leading to
  hypergammaglobulinemia
■ Cannot mount sufficient humoral immunity to
  common bacterial antigen

 Pathogenesis and Natural Course of the Disease       51
Monocyte Macrophage Activity
■ Circulating monocytes are generally normal in HIV
  infection
■ Cytopathic effect of HIV to monocyte macrophage
  is low
■ HIV can intensely replicate in monocyte
  macrophage cell line
■ There is defective function, like in antigen
  presentation, chemotaxis, secretion of IL-1 and in
  induction of T-cell response

Pathogenesis and Natural Course of the Disease     52
Humoral Immune Response
■ Neutralizing antibodies appear following primary
  viremia with CTLs
■ Antibodies are produced to multiple epitopes of
  HIV
■ HIV antibodies are used as diagnostic tool
■ Generally their preventive role is unknown




Pathogenesis and Natural Course of the Disease       53
Primary HIV Infection
■ Following primary infection there is initial viremia
■ The phenomena of dissemination of virus to
  lymphoid organs is the major factor in
  establishment of chronic and persistent infection
■ Whatever the route of entry the virus, it reaches a
  lymphoid organ, where it bases itself and replicates
  extensively
■ Intense replication brings about a burst of viremia
  which triggers HIV-specific antibody

 Pathogenesis and Natural Course of the Disease          54
Primary HIV Infection (2)
■ Primary viremia lasts several weeks
■ The set-point (steady state) plasma viremia at six
  months to one year correlates with disease
  progression (those with low set point develop
  advanced disease slowly)




 Pathogenesis and Natural Course of the Disease    55
Pathogenesis of HIV Infection: No
Progression with Low-level Viremia

              Primary HIV Chronic Non-progressive HIV Infection




                                                   CD4

                                            RNA Set Point ~ 103

                                                   RNA




 Pathogenesis and Natural Course of the Disease                   56
Pathogenesis: Average Progression
with Median-Level Viremia
                   Primary HIV          Slowly Progressive HIV     AIDS




                                         RNA Set Point ~104
                                                     RNA

                                                       CD4




                                          1        5          10

                                                   Years
 Pathogenesis and Natural Course of the Disease                           57
Pathogenesis: Rapid Progression
with High-Level Viremia
                Primary HIV            AIDS




                            RNA         RNA Set Point ~ 106




                          CD4



                                         2        3


                                              Years
 Pathogenesis and Natural Course of the Disease               58
HIV RNA Levels Predict Progression to
AIDS




 Pathogenesis and Natural Course of the Disease   59
Relating Disease Progression to Plasma
HIV-1 RNA Level and CD4 Cell Count

                Viral Load
                             1,000
                                                                                    100

                                           10,000
                                                                                    200


                                                              100,000
                                                                              300




                                                                        400


                    1000     900     800    700     600       500
                                                          +
                                                    CD4 COUNT

             Adapted with permission from Coffin. AIDS. 1996;10(suppl 3):S75-S84.


 Pathogenesis and Natural Course of the Disease                                           60
Chronic and Persistent Infection
■ HIV-specific antibody partially clears the virus
■ There is clinical latency
■ Initial clones of CD8 lymphocytes CTLs, which
  partially control viremia, are later lost
■ There is progressive drop in CD4 T-cells




 Pathogenesis and Natural Course of the Disease      61
Advanced HIV Disease
■ CD4 cells fall below critical level: <200cells/ml
■ Patients present with OIs or malignancy
■ Higher degree of viremia due to destruction of
  lymphoid organs




Pathogenesis and Natural Course of the Disease        62
Natural History of HIV Disease from HIV
Transmission to Death (no ARV)




            •   Fauci AS, Pantaleo G, Stanley, Weissman D. Immunopathogenic
                mechanisms of HIV infection. Ann Intern Med 1996;124:654-63.
Window Period: Untreated Clinical
Course
   Primary Acute HIV syndrome                                      antibody
                                                  Asymptomatic
   HIV
   infection                                                        viremia


                   --------------------------------------------PCR
                                                                P24
                                                                ELISA
                                        Time from a to b is the window period
         a                      b
     0     2    3 4
     Weeks since infection                                 years
Source: S Conway and J.G Bartlett, 2003

 Pathogenesis and Natural Course of the Disease                           64
Laboratory Markers of HIV Infection –
Immune Suppression
Markers of immunologic damage by HIV: subsets of
T-lymphocytes
■ Functional surface proteins (CD4 and CD8) used
  to count
■ Normal Values
     ■ Helper / CD4 + cell count = 400-1200
     ■ Suppressor/ CD8 + cell count = 400-800



 Pathogenesis and Natural Course of the Disease   65
Key Points
■ HIV infection is a chronic disease
■ The immune system is the target of HIV
■ Clinically there are different stages based on
  immunocompetence
■ During clinical latency, there is no virological
  latency




 Pathogenesis and Natural Course of the Disease      66
Key Points (2)
■ The effect of immune system delays the onset of
  clinical disease
■ HIV can be suppressed, but there is no cure
■ Ultimately the immune system is destroyed, with a
  few exceptions




 Pathogenesis and Natural Course of the Disease     67

								
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